Numerous patents disclose various 17.alpha.-hydroxy corticoids which are useful as topical anti-inflammatory agents. Various substituents and/or derivatives such as 2.alpha.-methyl, 9.alpha.-fluoro, 6.alpha.-methyl, .DELTA..sup.1,4, 16-alkyl and 6.alpha.-fluoro have been reported to enhance pharmacological activity.
In general, those substituents which enhance corticoid activity such as 6.alpha.-methyl, .DELTA..sup.1,4 or 9.alpha.-fluoro were also found to enhance resistance of the 17.alpha.-hydroxy corticoid to metabolic transformation by the liver; that is the more potent substituted steroids were more slowly metabolized.
In general, 21-halo steroids have been reported as providing enhanced activity and/or favorable ratio of topical anti-inflammatory activity to systemic side effects, see U.S. Pat. Nos. 3,721,687 and 3,992,422. U.S. Pat. No. 4,051,055 discloses 21-halo steroids but not as topical anti-inflammatory agents but as intermediates in the synthesis of corticoids. U.S. Pat. No. 3,502,700 discloses various 21-halo steroids as useful for their progestational activity and does not mention topical anti-inflammatory activity. All of the above 21-halo steroids were .DELTA..sup.4 - and .DELTA..sup.1,4 -9,21-dihalo-11.beta.-hydroxy-16-alkyl steroids. A number of these are mentioned as having an " . . . especially favourable topical anti-inflammatory activity and/or ratio of topical anti-inflammatory activity is glucocorticoid activity . . . ". In the specification of U.S. Pat. No. 3,721,687 a number of substituents are identified as being preferred or especially preferred. These include .DELTA..sup.1,4 ; 9.alpha.-chloro-11.beta.-hydroxy-16-methyl-17-propionate; 9.alpha.-fluoro- 11-hydroxy-16.alpha.-methyl-17-esters with at least 3 carbon atoms and 9.alpha.-fluoro-11-keto-16-methyl or -16-methylene steroids. A particularly preferred compound appears to be "9.alpha.,21-difluoro-16-methylene-17-propionyloxy-1,4-diene-3,11,20-trion e."
Virtually all the cortical steroids disclosed for topical anti-inflammatory activity are .DELTA..sup.4 or .DELTA..sup.1,4 steroids. U.S. Pat. No. 3,055,922 discloses a series of 5.alpha.-steroids which were alleged to retain the topical anti-inflammatory activity of the corresponding .DELTA..sup.4 - or .DELTA..sup.1,4 -steroids while the systemic activity was for all practical purposes eliminated. The applicants have now established that the "5.alpha." steroids of U.S. Pat. No. 3,055,922 were actually "5.beta.." This matter will be discussed fully in the Detailed Description of the invention.
Therefore, both U.S. Pat. Nos. 3,721,687 and 3,055,922 disclose a split between the topical anti-inflammatory activity and the systemic activity. However, U.S. Pat. No. 3,721,687 discloses that 17.alpha.-acyloxy-.DELTA..sup.1,4 -steroids have a good activity split while U.S. Pat. No. 3,055,922 discloses that 17.alpha.-hydroxy-5.alpha.-steroids have a good activity split. The present invention discloses that 17.alpha.-acyloxy-5.alpha.-steroids and 17.alpha.-acyloxy-5.beta.-steroids surprisingly and unexpectedly have an excellent activity split, and high topical anti-inflammatory topical/systemic ratio.
German Offen No. 2,905,674 discloses a process of transforming a 5.alpha.-pregnane to the corresponding .DELTA..sup.1,4 -17.alpha.-acylate which is the opposite of the present invention. The steps in the procedure include (1) protection of the 11.beta.-hydroxyl group as a trimethylsilyl (TMS) derivative (Example 1), (2) esterification of the 17.alpha.-hydroxyl group to give a 5.alpha.-17.alpha.-acyl-11.beta.-TMS steroid (Example 2), (3) dehydrogenation (oxidation) of the 5.alpha.-A ring to a .DELTA..sup.1,4 -A ring (Example 3) and (4) removal of the TMS protecting group (Example 4). In this process a 5.alpha.-17.alpha.-acyl steroid is disclosed but it does not have a free 11.beta.-hydroxyl group. In addition, the compound is not disclosed as having any useful pharmacological activity but only as an intermediate.